1. Field of the Invention
This invention is concerned with an improved process for the production of 1-[2-(dialkylamino)ethyl]-6-aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines (II), and more specifically for the production of 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benz odiazepine (IIC).
The compound, 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benz odiazepine (IIC) has been produced earlier in low yields by a variety of processes, e.g., in Ser. No. 550,120, filed Feb. 14, 1975, now U.S. Pat. No. 4,012,413, it is prepared by reduction of the corresponding acetamide: ##STR3## with borane, which produces simultaneous reduction of the 5,6-double bond and thus requires an additional oxidation step for the re-introduction of said double bond.
Another synthesis shown in this application Ser. No. 550,120 is the condensation of the 2-hydrazino compound: ##STR4## with .beta.-phthalimidopropionic acid: ##STR5## which provides: ##STR6## which upon treatment with hydrazine followed by reductive alkylation with formaldehyde provides the desired compound IIC. In the first of these two methods, compound IIC was obtained in yields of less than 15%. In the second method, although the overall yield was higher (35%-45%), several steps were involved and the large scale preparation of IIC was made difficult by the apparent instablity of the primary amine intermediate.
In application Ser. No. 657,461, now abandoned, a compound of the formula: ##STR7## is reacted under neutral conditions with a dimethylmethyleneammonium salt to give compound IIC in a yield of 20% to 30%. This process required heating the reactants at temperatures of from 50.degree.-90.degree. C. for from 1-2 days. It was usually necessary to separate the product (IIC) from biproducts and unreacted starting material by chromatography, an additional costly step unsuitable for large scale preparations.
It has now been discovered that compound IIC can be produced in yields of greater than 80%, when with the dimethylmethyleneammonium salt an acylating agent, such as a carboxylic acid halide or the anhydride of a strongly acidic carboxylic acid is used in catalytic amounts (5%-50%) of the molequivalents of the 1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine; alternatively, the dimethylmethyleneammonium salt can be prepared in situ, by reacting N,N,N',N',-tetramethyldiaminomethane with an acyl halide or acid anhydride, with the latter being in slight excess to fulfill the conditions for the presence of acyl halide or acid anhydride.
The new reaction can therefore be illustratively presented as follows: ##STR8## wherein R.sub.1 is alkyl of 1 to 3 carbon atoms, inclusive; wherein R.sub.2 is hydrogen, methyl or phenyl; wherein the ring A is unsubstituted, or monosubstituted with fluoro, chloro, bromo, nitro, trifluoromethyl or methylthio and wherein Ar is phenyl, o-chlorophenyl, o-fluorophenyl, 2,6-difluorophenyl, or 2-pyridyl.
The process of this invention comprises:
Treating a compound of formula I with an equivalent or slightly (5%-10%) larger amount of a selected dialkylmethyleneammonium salt which can be:
(A) prepared in advance by reacting N,N,N',N',-tetraalkyldiaminomethane and an acylating agent, such as, ##STR9## wherein R.sub.4 is phenyl or alkyl of 1 to 5 carbon atoms, inclusive, in which the alkyl moiety can be chlorinated or fluorinated and Y is chloro or bromo, or with an acid anhydride of the formula ##STR10## wherein R.sub.6 is defined as a chloro or fluoro-substituted alkyl of 1 to 5 carbon atoms, or even an alkyl chloroformate of the formula: EQU ClCOOR'
wherein R' is a lower alkyl of 1 to 4 carbon atoms.
(B) prepared in situ by the same reaction as shown under (A).
In either case the presence of a slight excess of the acylating agent, being between 5% and 50% molar excess over the calculated stoichiometric amount of N,N,N',N'-tetraalkyldiaminomethane, causes the reaction to proceed faster at a lower temperature and to a higher yield.